The losing streak continues in Alzheimer’s disease.
Boulder, Colorado-based Accera revealed Tuesday that the first of its Phase 3 trials for AC-1204 has fallen short of its primary endpoints in mild-to-moderate Alzheimer’s disease.
When Investment Rhymes with Canada
Canada has a proud history of achievement in the areas of science and technology, and the field of biomanufacturing and life sciences is no exception.
Dubbed NOURISH AD, the double-blind, randomized and placebo-controlled study ran for 26-weeks, with an optional 26-week open-label extension for patients. The primary and secondary endpoints focused on memory and cognition as measured by the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) as well as global function.
According to Accera CEO Charles Stacey, the disconnect between its encouraging Phase 2 data and the Phase 3 readout was a change in the formulation that decreased bioavailability.
“We recognize now that the primary reason for not meeting that primary efficacy outcome was the fact that our drug formulation had a problem associated with it that led to lower levels of the bioavailability,” Stacey said in a phone interview.
If accurate, it’s a frustrating conclusion to a late-stage trial involving 413 Alzheimer’s patients. The obvious question: Why were the changes made and why was the new formulation not thoroughly validated before patient dosing began?
“Small incremental changes in formulation during the course of a program development are not unusual,” Stacey explained. “The changes we were making, we thought at the time were immaterial and would not affect bioavailability. In hindsight, we now recognize that it did have that unintended consequence.”
For AC-1204 to work it has to raise plasma levels of ketone bodies.
Accera approaches Alzheimer’s as a metabolic condition, following literature that shows metabolic deficits arise in the brains of Alzheimer’s patients some 20-30 years before symptoms arrive. If the cells are unable to process glucose they are effectively starved, leading to cell death and potentially triggering amyloid-beta deposits.
The active compound in AC-1204 is derived from palm kernels. It contains medium chain triglycerides (MCTs), which stimulate the production of ketone bodies, an alternative fuel source that can be used by the brain when glucose aren’t available — or when they can’t be metabolized.
According to Stacey, the NOURISH AD trial did support the scientific principles of the program.
“Despite the overall outcome of the study, within posthoc exploratory analysis there were clear signs of efficacy within subpopulations of the data,” he said, though he wouldn’t elaborate on what subpopulations responded most favorably.
“What I can share is that it’s consistent with what we’ve previously seen and our plan is to take those findings and discuss them with the FDA first,” he said.
The silver lining is that the formulation error is an easy fix and AC-1204 has another shot on goal. Accera made the decision to run its Phase 3 trials sequentially, which pushes out a potential approval date but ensures that any findings (or failures) from the first trial can inform the second.
Accera remains a private company and Stacey said its financial backers have reiterated their support. He also emphasized that the NOURISH AD study showed top safety and tolerability.
Among the 77 drug candidates being investigated for Alzheimer’s, AC-1204 was closer to the line than most. That advantage is somewhat lost, as it looks to its next data readout in three or four years.
Next up in Alzheimer’s: Axovant’s late-stage MINDSET trial of intepirdine (RVT-101). That study is expected to read out in October of this year.
Photo: pictafolio, Getty Images
